Postchemotherapy Resections Research Articles

Primitive Embryonic-Type Neuroectodermal/Glandular Complexes in Testicular Germ Cell Tumors: A Mimic of Embryonic-Type Neuroectodermal Tumor.

Embryonic-type neuroectodermal elements are often intimately mixed with primitive endodermal-type glands, like those of yolk sac tumors, in germ cell neoplasia in situ (GCNIS)-derived germ cell tumors of the testis. Because the primitive glands mimic tubules or rosettes of embryonic-type neuroectodermal elements, these embryonic-type neuroectodermal/glandular complexes may be misinterpreted as pure lesions of embryonic-type neuroectodermal elements, which, if of sufficient size, may lead to a diagnosis of embryonic-type neuroectodermal tumor, despite that the criteria of the World Health Organization for a "somatic-type malignancy" are not met. A diagnosis of embryonic-type neuroectodermal tumor in the testis may lead to retroperitoneal lymphadenectomy even in clinical stage I patients, and in postchemotherapy resections indicates a poor prognosis. The distinction of the neuroectodermal and glandular elements is not always straightforward based on morphology alone. We, therefore, studied 34 testis-derived germ cell tumors with embryonic-type neuroectodermal/glandular complexes and 2 purely glandular yolk sac tumors to characterize the immunophenotypes and determine an efficient immunohistochemical panel to aid in this differential. We found that GFAP, synaptophysin, and paired-like homeobox 2B (PHOX2B) expression was specific to embryonic-type neuroectodermal elements, although PHOX2B had poor sensitivity. In contrast, positive reactions with antibodies directed against AFP, villin, and CDX2 were specific for the glandular elements, although CDX2 had poor sensitivity. Other markers, including AE1/AE3 cytokeratin, SALL4, glypican 3, SOX2, SOX11, CD56, INSM1, and neurofilament, proved less helpful because of their nonspecificity and/or poor sensitivity. We conclude that the optimal immunohistochemical panel for distinguishing the components of embryonic-type neuroectodermal/glandular complexes includes stains for synaptophysin, GFAP, villin, and AFP.

Outcomes in Patients With Postchemotherapy Residual Nonretroperitoneal Disease in Nonseminomatous Germ Cell Tumors

This case-control study assesses the association between teratoma in the primary tumor or postchemotherapy resections and survival outcomes.

Morphologic Changes in the Thymus Following Chemotherapy for Anterior Mediastinal Germ Cell Tumors: A Study of 91 Cases Emphasizing Pseudoneoplastic Features.

The interpretation of postchemotherapy resections of anterior mediastinal germ cell tumors plays a critical role in determining future patient management and prognosis. Treatment-related changes in the thymus may mimic residual teratoma or microcystic-pattern yolk sac tumor. There is limited extant information concerning therapy-related pseudoneoplastic thymic alterations. To provide diagnostic assistance to distinguish nonneoplastic thymic abnormalities secondary to chemotherapy from residual germ cell tumor. We retrospectively reviewed 91 resections of primary anterior mediastinal germ cell tumors with recognizable thymic gland following cisplatin-based chemotherapy. The cohort included 90 men and 1 woman (median age, 29 years). A spectrum of thymic epithelial alterations occurred, including cystic change (macrocysts [n = 21] or microcysts [n = 20]); hyperplasia with reactive atypia (n = 8); ciliated, mucinous, or columnar cell metaplasia (n = 3); and mature squamous metaplasia (n = 2). These changes were similar to so-called acquired multilocular thymic cysts, were often contiguous with and adjacent to normal thymic epithelium, and lacked the neoplastic-type atypia seen in teratomatous elements in this setting. In 1 case, confluent microcysts closely mimicked the appearance of yolk sac tumor but lacked other distinctive features of that neoplasm and its characteristic immunoreactivity. Recognition of therapy-induced thymic changes is important to avoid misinterpretation as residual teratoma or yolk sac tumor. Continuity with and proximity to benign thymic epithelium, absence of neoplastic-type atypia, and awareness of this phenomenon are important in avoiding this pitfall.

Features and Management of Late Relapse of Nonseminomatous Germ Cell Tumour

BackgroundLate relapse (LR) of nonseminomatous germ cell tumour (NSGCT) is uncommon, with limited data published. LR is defined as relapse occurring after a disease-free interval of 2 yr. ObjectiveTo review features of NSGCT LR in a UK tertiary centre. Design, setting, and participantsA total of 3064 patients were referred from January 2005 to December 2017. We identified patients who experienced LR after initial pathology demonstrated NSGCT and reviewed data for their original and LR presentation and management. Outcome measurements and statistical analysisOutcomes included time to LR measured from the date of diagnosis, and overall survival. This was assessed using Cox proportional Hazards modelling, with stratification or adjustment for potential confounders. Results and limitationsWe identified 101 patients with LR; the median time to LR was 96 mo. Forty-three patients (42.6%) experienced relapse after 10 yr. Univariable log-rank testing revealed that the median time to LR was significantly shorter for patients who had not received induction chemotherapy (iCTx; 54 mo, 95% confidence interval [CI] 48–108) than for those who did (112 mo, 95% CI 84–186; p = 0.04). Patients who had received iCTx were less likely to have elevated tumour markers (36% vs 46%) and more likely to undergo initial surgical resection at LR compared to CTx-naïve patients. Postpubertal teratoma (PPT), yolk sac, and dedifferentiated elements predominated for patients with iCTx exposure, whereas active GCT or fibrosis predominated in postchemotherapy resections for CTx-naïve patients at LR. Forty-one men underwent postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) as part of their initial treatment for metastatic disease. Of these, 20 experienced LR in the retroperitoneum, with 18 undergoing repeat RPLND as part of their LR management. Fifteen of the repeat RPLND histopathology specimens had a PPT component. There have been 23 deaths overall; survival was worse for patients presenting with symptoms (13/36, 33%) and those receiving CTx and no surgery (10/17, 59%) at LR. ConclusionsWhen LR of NSGCT occurs, it is frequently after an extended interval and is later among patients with prior iCTx, with PPT predominating. The high frequency of LR within the retroperitoneum following PC-RPLND reinforces the need for good-quality PC-RPLND. Patient summaryWe reviewed data for patients who had a late relapse of testicular cancer. We found that patients who did not receive chemotherapy as the first treatment for their initial diagnosis had a shorter time to relapse. Our results highlight the importance of long-term follow-up for testicular cancer.

Vasculogenic Mesenchymal Tumor: A Clinicopathologic and Molecular Study of 55 Cases of a Distinctive Neoplasm Originating From Mediastinal Yolk Sac Tumor and an Occasional Precursor to Angiosarcoma.

We report 55 postchemotherapy resections of primary nonseminomatous mediastinal germ cell tumors with prominent vasculogenic features showing the formation of rudimentary to well-developed neoplastic vessels within primitive mesenchyme. These cases represented 25% of a cohort of 221 such specimens. The patients were 19 to 49 years old (mean, 28 y) and 98% had serological evidence of yolk sac tumor. The vasculogenic lesions, felt to represent a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac, were further subdivided into teratoma with vasculogenic stroma (n=9), vasculogenic mesenchymal tumor (VMT) (n=42, further classified into low grade [n=24] and high grade [n=18]), and angiosarcoma (n=4). The distinction of teratoma with vasculogenic stroma from VMT was based solely on the greater extent of VMT (exceeding 1 low power [×4 objective] microscopic field), with both categories showing a spectrum of vessels lined by atypical endothelium in a nonendothelial neoplastic stroma that often also generated vascular walls comprised of atypical smooth muscle. The angiosarcomas showed stratification of highly atypical endothelial cells or anastomosing vessels lined by nonstratified but cytologically similar endothelium. Immunohistochemical studies supported the generation of neoplastic vessels from the tumor stroma, most commonly by the development of stromal clefts showing reactivity for podoplanin, CD34, and occasionally ERG, followed by the gradual development from the clefts of thin-walled vessels that later became encircled by stromal cells showing smooth muscle differentiation by immunohistochemistry. Occasionally, round collections of stromal erythrocytes became surrounded by stromal cells to generate blood vessels. Fluorescence in situ hybridization showed chromosome 12p copy number increase in both the endothelial component and stromal component in 8/9 VMT cases and in 1/1 angiosarcoma. On follow-up, no patient with teratoma with vasculogenic stroma had evidence of a subsequent vascular tumor or sarcoma, whereas 8 of the 35 (23%) patients with VMTs (2 low grade and 6 high grade) and meaningful follow-up developed sarcoma (1 angiosarcoma, 2 rhabdomyosarcomas, and 5 not further characterized). The difference between low-grade and high-grade tumors was of borderline significance (P=0.058). Two of the 4 patients with angiosarcoma died of metastatic angiosarcoma, with the other 2 disease-free at 6.8 and 7 years. Compared with the 165 patients with follow-up and no vasculogenic lesions, there was a highly significant (P=4.3×10-5) association of any vasculogenic lesion with sarcomatoid tumors during the clinical course of VMT patients. In addition, 5/46 patients with follow-up and vasculogenic lesions (11%) died of either leukemia or myelodysplastic syndrome compared with 2 of 166 (1%) lacking them (P=0.0012). Three of the 5 patients had identifiable immature hematopoietic cells within their vasculogenic lesions, but 4 other VMT patients with these did not develop leukemia or myelodysplasia. We conclude: (1) vasculogenic lesions are frequent in postchemotherapy resections of primary mediastinal germ cell tumors with yolk sac tumor components; (2) they mostly consist of neoplastic vessels in a stroma that also generates neoplastic vascular walls of smooth muscle; (3) VMTs are associated with an increased incidence of sarcomas, even though most vasculogenic lesions in this context do not meet criteria for angiosarcoma; (4) the presence of vasculogenic lesions in postchemotherapy resections of primary mediastinal germ cell tumors place patients at increased risk for leukemia or myelodysplasia.

A Clinicopathologic and Molecular Analysis of 34 Mediastinal Germ Cell Tumors Suggesting Different Modes of Teratoma Development.

Mediastinal teratomas are enigmatic; those in children and women are almost invariably benign but in men they may be benign or malignant. There are few data on the chromosome 12p status of mediastinal germ cell tumors (GCT), whereas increased 12p copy number is virtually uniform in malignant testicular GCTs. We therefore studied chromosome 12p copy number in 34 diverse mediastinal GCTs and correlated the results with morphology and follow-up to gain insight into possible pathogenesis. Four prepubertal (below 12 y) children (3 females and 1 male), 7 postpubertal females (14 to 52 y) and 6 postpubertal males (12 to 40 y old) had pure, previously untreated teratomas; 15 were mature and 2 had low-grade immaturity. All lacked 12p copy number increase and cytologic atypia, and most (14/17) showed organoid morphology. On follow-up of 16, 1 died of postoperative complications and the remaining 15 were disease free (1 to 119 mo, mean: 39 mo). Eight postpubertal males (19 to 44 y old) had pure teratomas in postchemotherapy resections; 5/8 showed 12p copy number increase. All 8 had distinct cytologic atypia, with organoid morphology in 3. On follow-up, 6 were disease free after surgical resection (1.5 to 94 mo, mean 38 mo); 1 died of disease at 14.5 months, and 1 was alive with metastases at 176 months. Two postpubertal patients, 1 male (29 y) and 1 female (31 y), had teratoma with secondary somatic-type malignancies, with positive 12p copy number increase in the former but not the latter. The man's tumor occurred after chemotherapy and was a nonorganoid teratoma with primitive neuroectodermal tumor and malignant glioma; the woman's was a previously untreated organoid teratoma with an undifferentiated carcinoma component. The man died of disease (16 mo) and the woman was alive with metastases (27 mo). Seven patients had resections for mixed GCTs (4) or pure nonteratomatous tumors, all after chemotherapy; 5/7 had positive 12p copy number increase. The teratoma component of the 2 cases having one showed distinct cytologic atypia and lacked organoid morphology. On follow-up, 1 died of disease (5 mo), 2 were alive with disease (1, 1.5 mo), 3 were disease free (1 to 43 mo; mean: 18 mo), and 1 was alive with unknown status (31 mo). Our results support that mediastinal teratomas likely develop from 2 separate pathways. Those in children, women and some men arise as pure neoplasms from a nontransformed precursor cell and, therefore, lack 12p copy number increase, show no cytologic atypia, often have organoid morphology and are benign. Common 12p copy number increase, uniform atypia, infrequent organoid structures and malignant behavior support that pure teratomas after chemotherapy in postpubertal males derive from a malignantly transformed precursor cell. Interestingly, we identified organoid pancreatic differentiation only in the benign group and neuroglia more commonly in the malignant teratomas.

Postchemotherapy changes in testicular germ cell tumours: biology and morphology.

Advances in modern chemotherapy and targeted treatments have resulted in lengthened survival in a variety of tumour types in the last decade. Increasingly in the 21st century, postchemotherapy resections are considered as a possible mode of treatment. Due to their exquisite chemosensitivity, resection of postchemotherapy masses has long been part of the armamentarium of treatment in testicular germ cell neoplasia, which has resulted in a variety of new morphological variants being described after treatment. Here we discuss the possible reasons for germ cell tumour chemosensitivity and hypotheses on the biological pathways leading to resistance to treatment, as well as an outline of the diverse morphology of those tumours which prove recalcitrant to standard treatment methods. The large range of morphologies and their diagnostic challenges may throw light upon the future problems to be encountered in non-germ cell solid tumour pathology, as the resection of postchemotherapy masses becomes increasingly important in patient management.

Many postchemotherapy sarcomatous tumors in patients with testicular germ cell tumors are sarcomatoid yolk sac tumors: a study of 33 cases.

Sarcomatoid neoplasms in patients with testicular germ cell tumors (TGCTs) may show diverse lineages and are usually attributed to "transformation" of teratoma, although origin from yolk sac tumor (YST) has also been suggested. We evaluated 33 sarcomatoid tumors from 23 TGCT patients that lacked specific features of a defined sarcoma subtype for a number of features, including: atypia (mild, moderate, severe), cellularity, tumor necrosis, mitotic index, stromal vascularity, cell profile (spindle or epithelioid), and stromal quality (myxoid and/or fibrous). Immunohistochemical staining analyses directed against cytokeratin (AE1/AE3), SALL4, glypican-3 (GPC3), α-fetoprotein (AFP), p63, glial fibrillary acidic protein (GFAP), CD34, MUC4, smooth muscle actin (SMA), desmin, caldesmon, and myogenin were performed. Staining intensity (0=negative, 1=weak, 2=moderate, 3=strong) and extent (0=<1%, 1=1% to 10%, 2=10% to 50%, 3=>50%) were scored. Tumor grade based on the French sarcoma grading system was assessed, with grades 2-3 considered high grade. Tumors with at least moderate intensity and >10% (+) cells for both AE1/AE3 and GPC3 were considered to be sarcomatoid YST (SYST); 22 tumors from 14 patients (ages 18 to 38 y, mean 27 y) met these criteria and were the focus of this study. All SYSTs occurred after chemotherapy (3 to 132 mo after TGCT diagnosis; mean 42.5 mo, median 30.5 mo). They had spindled (100%; 19 predominant) and epithelioid cells (77%; 3 predominant) in myxoid to fibrous stroma. Thirteen exhibited at least focally severe nuclear atypia. Distinctive tumor "ringlets" and intercellular basement membrane deposits (parietal YST differentiation) were common. In addition to positivity for AE1/AE3 and GPC3, 15/22 were SALL4 (+), 10/22 were at least focally CD34 (+), and 2/22 were focally p63 (+). Fifty percent exhibited smooth muscle differentiation as evidenced by desmin (8/19), caldesmon (2/4), and/or SMA (4/6) reactivity. AFP, MUC4, GFAP, and myogenin were negative in all cases. On follow-up, 8/14 patients died of disease at 7 to 217 months (mean 58 mo) after the initial SYST diagnosis, whereas 5/14 were alive and had no evidence of disease (ANED) at 1 to 259 months (mean 83 mo). One patient died of unrelated causes at 39 months. Of the 11 patients with high-grade tumors, 8 were dead of disease, 1 died of an unrelated cause, and 2 were ANED; all 3 patients with low-grade tumors were ANED at 41 to 262 months (mean 128 mo). We conclude that a high proportion of sarcomatoid tumors in postchemotherapy resections of TGCT patients are SYSTs. These typically occur several years after diagnosis and behave aggressively when high grade.

Abstract A78: Using primary osteosarcoma samples to study tumor heterogeneity

Abstract Osteosarcoma (OS) is an aggressive pediatric bone malignancy that affects 400 children per year in the United States. It has one of the lowest 5 yr. survival rates of any pediatric cancer. In order to gain a better understanding of the pathogenesis of OS, we have established a panel of patient derived xenografts (PDX). Through a three institution collaboration, we have obtained 52 OS patient samples, 38 pre-chemotherapy biopsies and 16 post induction chemotherapy resections. These samples were implanted into immunocompromised mice either subrenal or intradermal and allowed to expand. We were able to generate 20 PDX samples (38% take rate) and have characterized 7 of them. This includes one pre and post-chemo pair from the same patient. The PDX samples had similar histology to the original patient biopsy including formation of osteoid, which is a hallmark of OS. Tumor propagating cells (TPCs) are a rare subset of cells with in the tumor that are thought to contain the properties necessary to propagate and give rise to all cells found in the original tumor. TPCs are also thought to be resistant to chemotherapy and thus, it is important to identify and study these cells to gain a better understand the biology that underlies the TPCs ability to propagate the tumor. To identify the TPCs in OS, we selected a panel of cell surface markers that have been associated with TPCs in other cancer types and assessed for their expression across multiple OS PDX samples. CD49f, CD146 and CD90 were expressed heterogeneously in most PDX samples. There was also a high degree of overlap in the expression of these three markers in a subset of OS cells. To determine if the heterogenenous staining observed has a biological significance, we sorted CD49f positive and negative cells and implanted them in serial dilutions into immunocompromized mice. Although no difference in tumor instance was observed, CD49f + tumor cells formed significantly larger tumors than those arising from CD49f- tumor cells. Thus, CD49f expression may mark a more proliferative subset of cells within the bulk tumor. Further studies are currently ongoing to define the functional relevance of CD146 and CD90 expression and their role in tumor propagation and tumor morphology using OS PDX samples. To further characterize these OS PDX samples, we have employed RNA sequencing technology. To date we have obtained RNAseq on 4 pre-chemotherapy and 3 post-chemotherapy patient samples. Analysis of this dataset is ongoing and may provide insight into mechanisms of chemoresistance. Citation Format: Leanne C. Sayles, Justin Vincent-Tompkins, Charles Chan, Irving Weissman, E. Alejandro Sweet-Cordero. Using primary osteosarcoma samples to study tumor heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A78.

The Role of Axl in Ewing Sarcoma

ABSTRACT Aim: Ewing sarcoma (ES) is an aggressive form of primary bone cancer affecting mainly children and young adults. Despite intensive multimodal treatment, survival has not improved much during the last decade and therapeutic options in second line are scarce. Therefore, the search for novel, targeted therapeutic strategies has a high priority. Here, we investigated for the first time the expression and genetic aberrations of AXL, an oncogenic receptor tyrosine kinase (RTK), in ES and determined the efficacy of AXL-targeting on cell viability and migration in vitro. Methods: AXL and Gas6 (ligand) mRNA expression were determined by RT-PCR on 29 fresh-frozen ES patient samples. AXL protein expression was determined immunohistochemically in 36 tumors (primary tumors, post-chemotherapy resections, metastases and relapses) from 25 ES patients. Kaplan-Meier analysis (log-rank test) was performed to draw and evaluate the significance of survival curves. The AXL RTK domain and Gas6 were sequenced in 29 ES tumors. Six ES cell lines (ES1, ES2, ES4, ES7, ES8 and EW8) were treated in vitro with the specific AXL-inhibitor BGB324 (R428) and viability was analyzed with MTT-assays. In vitro migration assays were performed to investigate effects of BGB324 on ES cell migration. Results: Low, medium and high AXL mRNA expression was observed in 31% (n=9), 48% (n=14) and 21% (n=6) of ES samples, respectively. Gas6 was abundantly present in all specimens. Low, medium and high AXL protein expression was observed in 16% (n=6), 18% (n=7) and 34% (n=13) of ES samples. In primary tumors (n=15), high AXL expression correlated significantly with a worse overall survival (OS) compared to patients with lower expression (61 vs. 194 months, p=0.026). No genetic aberrations were observed in the AXL RTK domain or Gas6. BGB324 dose-dependently affected ES cell viability (IC50 0.79 - 2.13 mmol/L) and migratory potential (∼2 times delayed wound closure) in vitro. Conclusions: Our data suggest that AXL is a potential novel therapeutic target in ES. We are currently examining the effects of BGB324 on human derived ES xenografts in vivo. Because AXL-targeting drugs, such as BGB324, entered the phase of clinical trials, AXL targeting may potentially be of interest for further exploration in the clinical ES setting. Disclosure: All authors have declared no conflicts of interest.

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALK-inhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p = 0.031, z = -2.310, n = 11). In primary tumors (n = 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p = 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p = 0.078) and OS (88 vs. 128 months, p = 0.074) in patients with highest ALK levels (n = 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC50 1.22-3.59 μmol/L), NVP-TAE684 (IC50 0.15-0.79 μmol/L) and cabozantinib (IC50 2.69-8.27 μmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.

Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents

High-grade osteosarcoma is a malignant primary bone tumor with a peak incidence in adolescence. Overall survival (OS) of patients with resectable metastatic disease is approximately 20%. The exact mechanisms of development of metastases in osteosarcoma remain unclear. Most studies focus on tumor cells, but it is increasingly evident that stroma plays an important role in tumorigenesis and metastasis. We investigated the development of metastasis by studying tumor cells and their stromal context. To identify gene signatures playing a role in metastasis, we carried out genome-wide gene expression profiling on prechemotherapy biopsies of patients who did (n = 34) and patients who did not (n = 19) develop metastases within 5 years. Immunohistochemistry (IHC) was performed on pretreatment biopsies from 2 additional cohorts (n = 63 and n = 16) and corresponding postchemotherapy resections and metastases. A total of 118/132 differentially expressed genes were upregulated in patients without metastases. Remarkably, almost half of these upregulated genes had immunological functions, particularly related to macrophages. Macrophage-associated genes were expressed by infiltrating cells and not by osteosarcoma cells. Tumor-associated macrophages (TAM) were quantified with IHC and associated with significantly better overall survival (OS) in the additional patient cohorts. Osteosarcoma samples contained both M1- (CD14/HLA-DRα positive) and M2-type TAMs (CD14/CD163 positive and association with angiogenesis). In contrast to most other tumor types, TAMs are associated with reduced metastasis and improved survival in high-grade osteosarcoma. This study provides a biological rationale for the adjuvant treatment of high-grade osteosarcoma patients with macrophage activating agents, such as muramyl tripeptide.

Malignant germ cell tumors in childhood

Malignant germ cell tumors are a very heterogeneous group of neoplasms that have historically carried a poor prognosis. A review of the cooperative studies on malignant extracranial germ cell tumors in children was performed to update the progress in treatment and outcome for this rare group of tumors. The advent of platinum-based chemotherapy in the 1980s dramatically improved the prognosis for these tumors and allowed redefinition of risk groups. Chemotherapy regimens have been sequentially modified to reduce toxicity while maintaining survival. Surgical management has evolved from an aggressive en bloc resection at diagnosis to a more tailored approach, with resection and meticulous staging for low stage tumors at diagnosis and biopsy with neoadjuvant chemotherapy for advanced stage tumors. Improved surgical margins and prognosis are seen in post chemotherapy resections for high stage tumors. Large persisting masses after chemotherapy are often due to coexisting elements of benign teratoma, and aggressive attempts at resection are warranted in these patients with expectation of successful outcome.

Postchemotherapy resections of residual masses from metastatic nonseminomatous testicular germ cell tumors. A Spanish Germ Cell Group study

4525 Background: After chemotherapy for metastatic testicular tumors masses may remain. We analyze factors influencing histology and long-term evolution of patients with post-chemotherapy residual masses. Methods: 352 patients with nonseminomatous germ cell tumors with postchemotherapy residual masses and negative tumor markers were selected from the database of the Spanish Germ Cell Group between December 94 and February 04. Our protocol recommends surgical resection of masses larger than 2 cm. Patients with masses between 1 and 2 cm were offered follow-up or surgical resection. Of them 292 were finally operated: IGCCCG class: 137 (47%), 72 and 83 (28%) for good, intermediate and bad prognosis group respectively. Results: Median follow-up: 4 yrs. Thirty patients need 2 resections, 8 patients 3 and 3 patients 4 surgical maneuvers. Histology of masses: necrosis in 116 (40%), teratoma in 135 (46%), malignant tumor in 41 (14%). IGCCCG and Royal Marsdem class, histology of the primary, age and prechemotherapy size were correlated (X2 test) with histology of the residual masses. Lesions >5 cm before chemo and intermediate or bad prognosis group of the IGCCCG significantly correlated with necrosis. Statistically significant factors predicting teratoma were primary containing teratomatous elements, patient belonging to the good prognosis group and lesions below 5 cm before treatment. We did not identify factors correlated to malignant tumor. Analysis for survival: both IGCCCG class and malignant tumor at surgery were statistically significant in the multivariate analysis (p<0.001), whereas size, Royal Marsdem Class or histology of the primary were not. Five-year survival was 75%, 93% and 95% if malignant tumor, teratoma or necrosis were found respectively. Good, intermediate and bad prognosis group had a 5-yr survival of 97, 87 and 81% respectively. Conclusions: Our results suggest that persistence of small lesions after chemotherapy together with teratomatous elements in the primary predicts teratoma at surgery. IGCCCG class and persistence of malignant cells at surgery are the strongest prognostic factors for survival after resection of residual masses. No significant financial relationships to disclose.

Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer: Rick O, Bokemeyer C, Weinknecht S, Schirren J, Pottek T, Hartmann JT, Braun T, Rachud B, Weissbach L, Hartmann M, Siegert W, Beyer J, Department of Hematology and Oncology, Charité, Germany.

To assess the role of residual tumor resection performed after high-dose chemotherapy (HDCT) in patients with relapsed or refractory germ cell tumors (GCT). Between July 1987 and October 1999, postchemotherapy resections of residual tumors were performed in 57 patients who had been treated with HDCT for relapsed or refractory GCT and who had achieved a partial remission to this treatment. Complete resections of residual masses were achieved in 52 (91%) of 57 patients who were rendered disease free; in five (9%) of 57 patients, the resections were incomplete. Resection of a single site was performed in 39 (68%) of 57 patients, and the remaining 18 (32%) of 57 patients required interventions at two or more residual tumor sites. Necrosis was found in 22 (38%) of 57 patients, mature teratoma with or without necrosis was found in nine (16%) of 57 patients, and viable cancer with or without additional necrosis or mature teratoma was found in 26 (46%) of 57 patients. Viable cancer consisted either of residual germ cell or undifferentiated cancer in 22 (85%) of 26 patients, with additional non-GCT histologies in the remaining four patients. Patients with viable cancer had a significantly inferior outcome after surgery compared with patients with necrosis and/or mature teratoma even if all cancer was completely resected. Pulmonary lesions with a diameter of more than 2 cm were the only predictive variable for viable cancer in univariate analysis. Resections of all residual tumors should be attempted in patients with relapsed or refractory GCT and partial remissions after HDCT.

Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer.

To assess the role of residual tumor resection performed after high-dose chemotherapy (HDCT) in patients with relapsed or refractory germ cell tumors (GCT). Between July 1987 and October 1999, postchemotherapy resections of residual tumors were performed in 57 patients who had been treated with HDCT for relapsed or refractory GCT and who had achieved a partial remission to this treatment. Complete resections of residual masses were achieved in 52 (91%) of 57 patients who were rendered disease free; in five (9%) of 57 patients, the resections were incomplete. Resection of a single site was performed in 39 (68%) of 57 patients, and the remaining 18 (32%) of 57 patients required interventions at two or more residual tumor sites. Necrosis was found in 22 (38%) of 57 patients, mature teratoma with or without necrosis was found in nine (16%) of 57 patients, and viable cancer with or without additional necrosis or mature teratoma was found in 26 (46%) of 57 patients. Viable cancer consisted either of residual germ cell or undifferentiated cancer in 22 (85%) of 26 patients, with additional non-GCT histologies in the remaining four patients. Patients with viable cancer had a significantly inferior outcome after surgery compared with patients with necrosis and/or mature teratoma even if all cancer was completely resected. Pulmonary lesions with a diameter of more than 2 cm were the only predictive variable for viable cancer in univariate analysis. Resections of all residual tumors should be attempted in patients with relapsed or refractory GCT and partial remissions after HDCT.

Cystic trophoblastic tumor: a nonaggressive lesion in postchemotherapy resections of patients with testicular germ cell tumors.

Cystic trophoblastic tumor (CTT) is an uncommon lesion that is usually seen after chemotherapy in patients with testicular germ cell tumors. Its clinical significance has not been well studied. We identified 17 patients with CTT in retroperitoneal lymph node dissections (RPLNDs) after cisplatin-based chemotherapy for testicular germ cell tumors. None had other forms of persistent germ cell tumor except for teratoma, and no patient received additional chemotherapy after RPLND. At the time of RPLND, 7 patients were known to have had normal serum levels of beta-subunit of human chorionic gonadotropin (beta-hCG), whereas 5 had relatively mild elevations (1.6-165 mIU/mL, median, 8.0 mIU/mL). The CTTs consisted of circumscribed, small cysts, usually multifocal, lined by mostly mononucleated trophoblast cells with abundant eosinophilic cytoplasm, often with smudged nuclei and showing only infrequent mitotic figures. Although the epithelial lining was often stratified to several layers in thickness or formed intracystic papillary tufts, solid proliferations of trophoblast cells within the stroma were absent, as were clearly biphasic admixtures of mononucleated and multinucleated trophoblast cells. The cysts were either empty or contained fibrinoid material and were set in a hypocellular, fibrous stroma with adjacent teratoma. Stains for hCG highlighted rare cells. On follow-up of 15 patients, 11 were disease free (mean, 80 months). Three recurred with serum alpha-fetoprotein elevations at 25, 31, and 107 months, respectively, and one with beta-hCG elevation at 2 months. The latter patient, however, also had unresected mediastinal tumor postchemotherapy. We conclude that the finding of CTT in postchemotherapy resections does not warrant additional chemotherapy. Its clinical significance appears similar to that of residual teratoma.

The risk of nephrectomy during local control in abdominal neuroblastoma

Methods : Eight hundred sixty-eight children presenting from 1981 to 1991 were treated on five multiagent chemotherapy protocols by members of the Pediatric Oncology Group for advanced-stage neuroblastoma with large primary tumors crossing the midline or distant metastasis. Of these children, 696 had abdominal (adrenal or paravertebral) primary tumors. One hundred sixteen children underwent greater than 50% surgical resection of these abdominal primary tumors before chemotherapy, and 233 underwent similar surgery after induction chemotherapy. Results: Among the 349 who underwent surgical resection, 52 children (14,9%) had nephrectomy or renal infarction during surgery for local control. There was a 25% incidence among those with initial resection (29 patients) and a 9.9% incidence in the postchemotherapy resections (23 patients). Reasons for nephrectomy given by the surgeons included direct involvement of the kidney by adjacent tumor (17 children), clinical impression that the tumor was a Wilms' tumor (11 children), renal vessels could not be separated from the tumor (10 children), extensive tumor surrounding the kidney (8 children), postoperative renal infarction (4 children), marked decrease in unilateral renal function after chemotherapy (1 child), and position of the tumor posterior to the kidney and vena cava making resection without nephrectomy impossible (1 child). Of the patients undergoing nephrectomy, four children had an upper pole nephrectomy in conjunction with their adrenalectomy and resection of the tumor. Pathological review of the resected tumor available in 47 cases demonstrated direct involvement of the renal parenchyma in 18 cases (38% of the nephrectomies) and in 5.2% of those undergoing resection. In children undergoing initial resection, the risk for nephrectomy (as calculated by the methods described by Gart) was more than twice compared with those undergoing resection after chemotherapy ( P = .012; odds ratio, 2.32; 95% confidence interval of 1.23 to 4.42). Conclusions: This review confirms that renal parenchymal involvement does occur in a significant number of children with abdominal neuroblastoma. It also suggests that preoperative chemotherapy may decrease the number of nephrectomies required to achieve a total or subtotal resection.

Postchemotherapy resections of residual masses from metastatic non-seminomatous testicular germ cell tumors

To analyse the frequencies of histological findings, predictive factors for the presence of undifferentiated tumor and variables influencing the survival of patients with non-seminomatous germ cell tumors who underwent secondary resection of residual masses after cisplatin-based combination chemotherapy. 134 patients with a median age of 26 years (15-47) undergoing at least one surgical intervention at Hannover University Medical School were included. One hundred nine patients had received first-line chemotherapy and 25 underwent surgery after second-line chemotherapy. After first-line chemotherapy the distribution of histological findings was 52% necrosis, 27% differentiated teratoma and 21% undifferentiated tumor for 82 patients with marker negative PR (PRm-). Incompletely resected mass and failure to achieved complete tumor marker normalisation were significantly associated with the finding of undifferentiated tumor. Five-year progression-free survival rates according to histological findings were 78%, 67% and 66% for necrosis, differentiated teratoma and undifferentiated tumor. Patients with undifferentiated tumor in the resected specimen routinely received postoperative additional chemotherapy. Factors associated with a worse overall survival were progressive disease within three months, persistent AFP elevation prior to surgery, prechemotherapy elevated LDH levels or mediastinal lymph node involvement at primary diagnosis. In 8 of 27 patients (30%) undergoing multiple resections at different sites a dissimilar histology was found. In the 25 patients operated after salvage chemotherapy undifferentiated tumor was found in 80%. A five-year survival of 44% compared to 80% after first-line chemotherapy was achieved. Resection of residual tumors after first-line chemotherapy remains essential in the treatment of metastatic testicular cancer. Undifferentiated tumor may still be found in 20% of patients despite achieving PRm-after first-line chemotherapy. Necrosis is found in only 50% of marker normalized patients after first-line and approximately 30% after second-line chemotherapy. Future studies have to prove whether the combination of clinical prognostic factors and the use of PET-scanning will allow to spare subsets of patients from secondary resection.